Isoquinoline derivatives and isoquinoline combinatorial libraries

• US 5,874,443 A
• Filed: 10/18/1996
• Issued: 02/23/1999
• Est. Priority Date: 10/19/1995
• Status: Expired due to Fees

• Current Assignee: Lion Bioscience AG (2invest AG)
• Original Assignee: Trega Biosciences, Inc. (2invest AG)
• Inventors: Kiely, John S., Griffith, Michael C.
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US08/734,516
• Time in Patent Office: 858 Days
• Field of Search: 546/141, 514/309
• US Class Current: 506/15
• CPC Class Codes: C07D 217/26 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The present invention provides the synthesis of heterocyclic compounds based on the isoquinoline ring. More specifically, the invention provides novel isoquinolines as well as novel libraries comprised of many such compounds, and methods of synthesizing the libraries.

Claims

1. A single isoquinoline compound of the formula:

##STR13## wherein;

R¹ is selected from the group consisting of C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₂ to C₇ alkenyl, C₂ to C₇ substituted alkenyl, C₂ to C₇ alkynyl, C₂ to C₇ substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, phenyl, substituted phenyl, substituted naphthyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl and a group of the formula;

##STR14## wherein;

n and m are independently selected from a number 0 to 6; and

Ar is an aryl group selected from the group consisting of phenyl, substituted phenyl, heteroaryl and substituted heteroaryl;

R² is selected from the group consisting of hydrogen atom, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, C₂ to C₇ alkenyl, C₂ to C₇ substituted alkenyl, C₂ to C₇ alkynyl, C₂ to C₇ substituted alkynyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cylcoalkenyl, C₅ to C₇ substituted cycloalkenyl, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl and a heterocyclic ring;

R³, R⁴, R⁵ and R⁶ are independently selected from the group consisting of a hydrogen atom, halo, hydroxy, protected hydroxy, cyano, nitro, carboxylic acid, C₁ to C₆ alkyl, C₂ to C₇ alkenyl, C₂ to C₇ alkynyl, C₁ to C₆ substituted alkyl, C₂ to C₇ substituted alkenyl, C₂ to C₇ substituted alkynyl, C₁ to C₇ alkoxy, C₁ to C₇ acyloxy, C₁ to C₇ acyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, C₃ to C₇ substituted cycloalkenyl, a heterocyclic ring, C₇ to C₁₂ phenylalkyl, C₇ to C₁₂ substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, C₁ to C₄ alkylthio, C₁ to C₄ alkylsulfonyl, C₁ to C₄ alkylsulfoxide, phenylthio, substituted phenylthio, phenylsulfoxide, substituted phenylsulfoxide, phenylsulfonyl and substituted phenylsulfonyl;

X is selected from the group consisting of hydroxy, protected carboxy, amino, protected amino, (monosubstituted)amino, (disubstituted)amino, an amino acid, aniline, substituted aniline and an amino-substituted heterocyclic ring;

Y is selected from the group consisting of CO₂ H, SH, NHR⁷ and C(O)NHR⁷, wherein R⁷ is selected from the groups consisting of a hydrogen atom, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl;

or

a salt of the isoquinoline compound.

2. The single isoquinoline compound of claim 1, wherein:

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s)-1-(amino)-1,2-ethyl, (s)-1-(amino)-1,5-pentyl, (r)-(1-methyl)-1,2-ethyl, (s)-(1-(methyl)-1,2 ethyl), ##STR15## R² is selected from the group consisting of 1,4-benzodioxan-6-yl, 1-methylindole-3-yl, 2,3-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2-thiophen-yl, 3,4-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-(4-methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-pyridinyl, 3-thiophen-yl, 4-(3-dimethylaminopropoxy)phenyl, 4-(dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-biphenyl, 4-bromo-2-thiophenyl, 4-cyanophenyl, 4-methoxy-1-naphthyl, 4-nitrophenyl, 4-pyridinyl, 5-(4'"'"'-methoxybenzyl)-furan-2-yl, 5-bromo-4-hydroxy-3-methoxyphenyl, 5-nitro-2-furyl, 6-methyl-2-pyridinyl and phenyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is selected from the group consisting of aminocyclopropyl, aminoisopropyl, 3-aminopropyl, aminoethanolyl, (aminomethyl)cyclopropyl, pyrrolidyl, aminodiethyl, amino-2-methoxyethyl, aminocyclopentyl, piperidinyl, 1-(pyrrolidin-3-ol), aminoamyl, amino-2-(N,N-dimethyl)ethyl, azetidinyl, 2-aminofurfuryl, aminodiallyl, 2-aminothiazolyl, 1-aminopiperidinyl, 4-methylpiperazinyl, 4-aminomorpholinyl, aminodiethanol, 2-(aminomethyl)pyridinyl, histaminyl, 1-(2-aminoethyl)pyrrolidinyl, 1-amino-4-methylpiperazinyl, tris(hydroxymethyl)aminomethyl, 1-aminopyrrolidinyl, 1-(3-aminopropyl)imidazolyl, 1-(2-hydroxyethyl)piperazinyl, (+)-3-hydroxy piperidine, (s)-1-amino-2-(methoxymethyl)pyrrolidine, 1-amino-4-(2-hydroxyethyl)piperazinyl, trans-aminocyclohexan-2-olyl, tryptaminyl, 1-aminomethyladamantanyl, amino-2-(trimethylammonium)ethyl, α

-N-glycinyl, α

-N-lysinyl, α

-N-aspartyl, α

-N-tyrosinyl, α

-N-serinyl, (+)-3-aminopropyl-1,2-diol, (-)-3-amino-propyl-1,2-diol, (+)-aminotetrahydrofurfuryl, (-)-aminotetrahydrofurfuryl, (+)-exo-2-aminonorbornanyl, (-)-exo-2-aminonorbornanyl, cis-decahydroquinolinyl, trans-decahydroquinolinyl, (+)-3-aminoquinuclidinyl and (-)-3-aminoquinuclidinyl; and

Y is C(O)NH₂.

3. The isoquinoline compound of claim 2, wherein X is 1-aminomethyladamantanyl.

5. The isoquinoline compound of claims 3 or 4, wherein R² is 5-(4'"'"'-methoxybenzyl)-furan-2-yl.

6. The isoquinoline compound of claim 5, wherein R¹ is 1,6-hexyl.

7. The isoquinoline compound of claim 1, wherein:

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s)-1-(amino)-1,2-ethyl, (s)-1-(amino)-1,5-pentyl, (r)-(1-methyl)-1,2-ethyl, (s)-(1-(methyl)-1,2-ethyl), ##STR18## R² is selected from the group consisting of 1,4-benzodioxan-6-yl, 1-methylindole-3-yl, 2,3-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2-thiophen-yl, 3,4-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-(4-methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-pyridinyl, 3-thiophen-yl, 4-(3-dimethylaminopropoxy)phenyl, 4-(dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-biphenyl, 4-bromo-2-thiophen-yl, 4-cyanophenyl, 4-methoxy-1-naphthyl, 4-nitrophenyl, 4-pyridinyl, 5-(4'"'"'-methoxybenzyl)-furan-2-yl, 5-bromo-4-hydroxy-3-methoxyphenyl, 5-nitro-2-furyl, 6-methyl-2-pyridinyl and phenyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is selected from the group consisting of anilinyl, 2-fluoroanilinyl, 3-fluoroanilinyl, 4-fluoroanilinyl, 2-chloroanilinyl, 3-chloroanilinyl, 4-chloroanilinyl, 2-bromoanilinyl, 3-bromoanilinyl, 4-bromoanilinyl, 2-methoxyanilinyl, 3-methoxyanilinyl, 4-methoxyanilinyl, 2-hydroxyanilinyl, 3-hydroxyanilinyl, 4-hydroxyanilinyl, 2-carboethoxyanilinyl, 3-carboethoxyanilinyl, 4-carboethoxyanilinyl, 2-trifluoromethylanilinyl, 3-trifluoromethylanilinyl, 4-trifluoromethylanilinyl, 2-dimethylaminoanilinyl, 3-dimethylaminoanilinyl, 4-dimethylaminoanilinyl, 2-phenoxyanilinyl, 3-phenoxyanilinyl, 4-phenoxyanilinyl, 3,4-methylenedioxyanilinyl, 2,3-methylenedioxyanilinyl, 2,3-difluoroanilinyl, 2,3-dibromoanilinyl, 3,4-dibromoanilinyl, 2,3-dimethoxyanilinyl, 3,4-dimethoxyanilinyl, 1-amino-5,6,7,8-tetrahydronaphthyl, 2-hydroxy-3-amino 5,6,7,8-tetrahydronaphthyl, 2-aminonaphthyl, 1-amino-4-chloronaphthyl, 1-amino-4-bromonaphthyl, 5-amino-1-hydroxynaphthyl, 1-amino-2-hydroxynaphthyl, 5-aminoindanyl, 1-aminofluorenyl, 2-aminofluorenyl and N-methylanilinyl; and

Y is C(O)NH₂.

4. A single isoquinoline compound of the formula:

##STR16## wherein;

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s)-1-(amino)-1,2-ethyl, (s)-1-(amino)-1,5-pentyl, (r)-(1-methyl)-1,2-ethyl, (s)-(1-(methyl)-1,2 ethyl), ##STR17## R² is selected from the group consisting of 1,4-benzodioxan-6-yl, 1-methylindole-3-yl, 2,3-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2-thiophen-yl, 3,4-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-(4-methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-pyridinyl, 3-thiophen-yl, 4-(3-dimethylaminopropoxy)phenyl, 4-(dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-biphenyl, 4-bromo-2-thiophenyl, 4-cyanophenyl, 4-methoxy-1-naphthyl, 4-nitrophenyl, 4-pyridinyl, 5-(4'"'"'-methoxybenzyl)-furan-2-yl, 5-bromo-4-hydroxy-3-methoxyphenyl, 5-nitro-2-furyl, 6-methyl-2-pyridinyl and phenyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is (aminomethyl)cyclohexyl; and

Y is C(O)NH₂.

8. A single isoquinoline compound or a library of an approximately equimolar mixture of two or more compounds of the formula:

##STR19## wherein;

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,3-propyl, 1,4-butyl, 1,5-pentyl, 1,6-hexyl, (S)-1-amino-1,2-ethyl, (S)-1-amino-1,5-pentyl, (R)-1-methyl-1,2-ethyl, (S)-1-methyl-1,2-ethyl, ##STR20## R² is selected from the group consisting of phenyl, 2-bromophenyl, 2-cyanophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-bromophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 4-acetamidophenyl, 4-bromophenyl, 4-carboxyphenyl, 4-cyanophenyl, 4-(3-dimethylaminopropoxy)phenyl, 4-fluorophenyl, 4-(dimethylamino)phenyl, 4-hydroxyphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-(methylcarboxylate)phenyl, 4-methylsulphonylphenyl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-propoxyphenyl, 4, (trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 3,5-dihydroxyphenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2-chloro-5-nitrophenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl, 3-bromo-4-fluorophenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3-nitro-4-chlorophenyl, 3-hydroxy-4-methoxyphenyl, 3-hydroxy-4-nitrophenyl, 4-methoxy-3-(sulfonyl)phenyl, 3-methyl-4-methoxyphenyl, 2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxy-5-nitrophenyl, 1,4-benzodioxan-6-yl, 2,3-(methylenedioxy)phenyl, 3,4-(methylenedioxy)phenyl, 3,4-(methylenedioxy)-6-nitrophenyl, 8-hydroxyjulolidin-9-yl, 3-(3,4-dichlorophenoxy)phenyl, 3-(4-methoxyphenoxy)phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 4-methoxy-1-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 8-hydroxyquinolin-2-yl, 9-ethyl-3-carbazolyl, 2-thiophen-yl, 3-thiophen-yl, 5-methyl-2-thiophen-yl, 2-furyl, 3-furyl, 5-methyl-2-furyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 6-methyl-2-pyridinyl, pyrrole-2-yl, 1-methyl-2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 5-(4'"'"'-methoxybenzyl)-2-furyl, and 5-nitro-2-furyl;

R³,R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is selected from the group consisting of pyridoxamino, 4-(dimethylamino)benzylamino , 2-chloro-4-fluoroanilino, 3-pyridylmethylamino, 4-(dimethylamino)anilino, 1-adamantanemethylamino, 4-isopropylanilino, 3,4-dichlorobenzylamino, N-benzylethanolamino, 1-(α

,α

,α

-trifluoro-m-tolyl)piperazino, 4-nitrobenzylamino, 5-indanylamino, cyclohexylamino, 1-(2-pyridyl)piperazino, 4-methoxyphenethylamino, 1-naphthalenemethylamino, 2,4-dimethoxybenzylamino, (±

)-exo-2-norbornaneamino, 2-(2-chlorophenyl)ethylamino, 2-(4-methoxyphenyl)-2-phenylethylamino, 1,4-benzodioxan-6-amino, 5-bromo-2-fluorobenzylamino, 4-pyridylmethylamino, 1-phenylpiperazino, 2-fluoreneamino, 3,4-dimethoxybenzylamino, 2-(4-chlorophenyl)ethylamino, diphenylmethylamino, phenethylamino, N-benzylmethylamino, 4-iodoanilino, 3-nitrobenzylamino, (±

)-endo-2-norbornaneamino, 2-(3-chlorophenyl)ethylamino, 3-phenyl-1-propylamino, 3,5-dimethylanilino, 1,2,3,4-tetrahydroisoquinolino, 1,3,3-trimethyl-6-azabicyclo 3.2.1!octyl, 2-chloro-5-methylanilino, 3-chloro-4-methoxyanilino, 4-(4-methoxyphenyl)-4-phenylpiperidino, 5-fluoro-2-methylanilino, 4-phenoxyanilino, tryptamino, cycloheptylamino, 2,4-difluorobenzylamino, 2-fluoro-5-methylanilino, 3,4-difluorobenzylamino, 1-methyl-3-phenylpropylamino, 2,4-dichlorophenethylamino, 2-indanamino, 3,4,5-trimethoxybenzylamino, 2-bromobenzylamino, 2-bromo-4-methylanilino, trans-2-phenylcyclopropylamino, 3-amino-2,6-dimethoxypyridino, 5-chloro-2-methoxyanilino, 2-iodoanilino, 2,3-dimethoxybenzylamino, 2,6-difluorobenzylamino, 2,4-dimethoxyanilino, 4-chloro-2-methoxy-5-methylanilino, 1-amino-4-bromonaphthalene, 3-trifluoromethylbenzylamino, 3-chloro-2-methylanilino, 3-carboxamidoanilino, 2-fluorophenethylamino, 3-bromobenzylamino, 3-iodoanilino, 3-phenoxyanilino, 3,4-dimethoxyphenethylamino, 4-morpholinoanilino, 2-ethoxyanilino, tyramino, 2-trifluoromethylbenzylamino, 4-bromobenzylamino, 4-pentylanilino, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolino, 3-(1-(4-methoxyphenyl)ethyl)anilino, 1-adamantanamino, 2-thiazoleamino, 3-hydroxyanilino, 2-(4-aminophenyl)-6-methylbenzothiazolo, 3-methylsulphonylanilino, 4-propylanilino, 2-fluoro-4-methylanilino, 4-chlorobenzylamino, 3-fluorobenzylamino, 4-bromo-3-methylanilino, (±

)-α

-(methylaminomethyl)benzyl alcohol, 5,6,7,8-tetrahydronaphthalene-1-amino, 3-methylbenzylamino, 4-(methylmercapto)anilino, 5-chloro-2-methylanilino, 4-(diethylamino)anilino, (±

)-α

-methylbenzylamino, 2-chlorobenzylamino, 4-fluorobenzylamino, 2-methoxybenzylamino, 2-methylbenzylamino, 3-bromo-4-methylanilino, 4-fluorophenethylamino, 4-ethoxyanilino, 2,5-difluorobenzylamino, 2,3-dimethylanilino, benzylamino, 4-aminopyridino, 4-chloroanilino, 3-fluorophenethylamino, 4-bromoanilino, 4-hydroxyanilino, 4-bromo-2-methylanilino, 2-benzothiazolamino, 6-methoxybenzothiazol-2-amino, 4-methylbenzylamino, 2,4-dimethylanilino, 6-fluorobenzothiazol-2-amino, 3-(methylmercapto)anilino, 2-methylanilino, 4-picolin-2-amino, 3-chloro-4-fluoroanilino, 4-fluoroanilino, 4-methoxybenzylamino, 3-ethoxyanilino, 4-methoxy-2-methylanilino, 4-methylanilino, 2,5-dimethylanilino, 2-methoxyanilino, 2-fluoroanilino, 3,5-dimethoxyanilino, 2-methoxy-5-methylanilino, 2-methoxy-5-nitroanilino, 2-(methylmercapto)anilino, cytosino, 3-trifluoromethylanilino, anilino, 3,4-dimethylanilino, 3,4,5-trimethoxyanilino, 2,5-dimethoxyanilino, 3-fluoroanilino, 3,4-dimethoxyanilino, 4-carboxamidoanilino, 2,4-difluoroanilino, 3-methoxyanilino, and 4-methoxyanilino; and

Y is C (O) NH₂.

9. A single isoquinoline compound or a library of an approximately equimolar mixture of two or more compounds of the formula:

##STR21## wherein;

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,3-propyl, 1,4-butyl, 1,5-pentyl, 1,6-hexyl, (S)-1-amino-1,2-ethyl, (S)-1-amino-1,5-pentyl, (R)-1-methyl-1,2-ethyl, (S)-1-methyl-1,2-ethyl, ##STR22## R² is selected from the group consisting of phenyl, 2-bromophenyl, 2-cyanophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-bromophenyl, 3-(4-methoxybenzyl)phenyl, 3-cyanophenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 4-(N-ethylamino)anilino, 4-bromophenyl, 4-(4-methoxybenzyl)phenyl, 4-cyanophenyl, 4-(3-dimethylaminopropoxy)phenyl, 4-fluorophenyl, 4-(dimethylamino)phenyl, 4-hydroxyphenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-methylsulphonylphenyl, 4-(methylthio)phenyl, 4-nitrophenyl, 4-propoxyphenyl, 4-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 3,5-dihydroxyphenyl, 3,5-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2-chloro-5-nitrophenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl, 3-bromo-4-fluorophenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3-nitro-4-chlorophenyl, 3-hydroxy-4-methoxyphenyl, 3-hydroxy-4-nitrophenyl, 4-methoxy-3-(sulfonyl)phenyl, 3-methyl-4-methoxyphenyl, 2,3,4-trifluorophenyl, 2,3,5-trichlorophenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-methoxy-4-hydroxy-5-bromophenyl, 3-methoxy-4-hydroxy-5-nitrophenyl, 1,4-benzodioxan-6-yl, 2,3-(methylenedioxy)phenyl, 3,4-(methylenedioxy)phenyl, 3,4-(methylenedioxy)-6-nitrophenyl, 8-hydroxyjulolidin-9-yl, 3-(3,4-dichlorophenoxy)phenyl, 3-(4-methoxyphenoxy)phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 4-methoxy-1-naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 8-hydroxyquinolin-2-yl, 9-ethyl-3-carbazolyl, 2-thiophen-yl, 3-thiophen-yl, 5-methyl-2-thiophen-yl, 2-furyl, 3-furyl, 5-methyl-2-furyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 6-methyl-2-pyridinyl, pyrrole-2-yl, 1-methyl-2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 5-(4'"'"'-methoxybenzyl)-2-furyl, and 5-nitro-2-furyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is selected from the group consisting of anilino, 2-fluoroanilino, 2-methoxyanilino, 2-chlorobenzylamino, 2-methoxybenzylamino, 2-trifluoromethylbenzylamino, 3-fluoroanilino, 3-methylanilino, 3-trifluoromethylanilino, 3-(methylmercapto)anilino, 3-trifluoromethylbenzylamino, 3-methylbenzylamino, 4-propylanilino, 4-pentylanilino, 4-(methylmercapto)anilino, 4-fluorobenzylamino, 4-methoxybenzylamino, 4-methylbenzylamino, 3-(1-(4-methoxyphenyl)ethyl)anilino, 4-chloroanilino, 2,3-dimethylanilino, 4-methoxyanilino, 2,5-dimethoxyanilino, 3-chloro-4-fluoroanilino, 3-bromo-4-methylanilino, 3,4-dimethoxyanilino, 3,4-dimethylanilino, 3,5-dimethoxyanilino, 2-methylanilino, 3,4-dimethoxybenzylamino, 3,4-dichlorobenzylamino, 2-(3-chlorophenyl)ethylamino, 4-methoxyphenethylamino, N-benzylethanolamino, aminodiphenylmethane, 1-phenylpiperazino, 1-(α

,α

,α

-trifluoro-m-tolyl)piperazino, 1,4-benzodioxan-6-amino, 4-(aminomethyl)pyridino, 3-(aminomethyl)pyridino, 1-(2-pyridyl)piperazino, cycloheptylamino, cyclohexylamino, 5-fluoro-2-methylanilino, 3-(aminomethyl)anilino, 1-methyl-3-phenylpropylamino, 1-adamantanemethylamino, 1,3,3-trimethyl-6-azabicyclo 3.2.1!octyl, 2-ethoxyanilino, 4-isopropylanilino, 3-phenyl-1-propylamino, trans-2-phenylcyclopropylamino, 3-nitrobenzylamino, 4-bromobenzylamino, 2-bromobenzylamino, 3-bromobenzylamino, 4-ethoxyanilino, 2-indanamino, 2,6-dimethoxypyridine-3-amino, 4-nitrobenzylamino, 4-hydroxyanilino, 5-bromo-2-fluorobenzylamino, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolino, 2-adamantanamino, 2,4-dimethoxybenzylamino, 3-methylsulphonylanilino, 3-(dimethylamino)anilino, 4-(dimethylamino)anilino, pyridoxamino, 2-fluorophenethylamino, 3-fluorophenethylamino, 4-fluorophenethylamino, 2,4, dichlorophenethylamino, 3-iodoanilino, 3-chloro-2-methylanilino, 5-chloro-2-methoxyanilino, 4-methoxy-2-methylanilino, 2,4, dimethoxyanilino, 2,5-dimethylanilino, 2-fluoro-5-methylanilino, 2,3-dimethoxybenzylamino, 2,4-difluorobenzylamino, 2,5-difluorobenzylamino, 2,6-difluorobenzylamino, 5-chloro-2-methylanilino, 2,4-dimethylanilino, 2-fluoro-4-methylanilino, 3-phenoxyanilino, 4-phenoxyanilino, 2-fluorenamino, 1-naphthalenemethylamino, 3-hydroxyanilino, 4-aminopyridino, 4-picolin-2-amino, 5-indanamino 1-amino-5,6,7,8-tetrahydronaphthalene, tyramino, 1-(4-methoxyphenyl-1-phenylethyl-2-amino, 1-adamantanamino, 4-(4-methoxyphenyl)-4-phenylpiperidino, 4-chloro-2-methoxy-5-methylanilino, 4-morpholinoanilino, 3-chloro-4-methoxyanilino, hydroxyl, (±

)-exo-2-norbornanamino, (±

)-endo-2-norbornanamino, and (±

)-α

-methylbenzylamino; and

Y is selected from the group consisting of CH₂ OH, SH, NHR⁷ and CH₂ NHR⁷, wherein R⁷ is selected from the groups consisting of a hydrogen atom, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl.

10. An isoquinoline library of an approximately equimolar mixture of two or more compounds of the formula:

##STR23## wherein;

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s)-1-(amino)-1,2-ethyl, (s)-1-(amino)-1,5-pentyl, (r)-(1-methyl)-1,2-ethyl, (s)-(1-(methyl)-1,2 ethyl), ##STR24## R² is selected from the group consisting of 1,4-benzodioxan-6-yl, 1-methylindole-3-yl, 2,3-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2-thiophen-yl, 3,4-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-(4-methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-pyridinyl, 3-thiophen-yl, 4-(3-dimethylaminopropoxy)phenyl, 4-(dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-biphenyl, 4-bromo-2-thiophenyl, 4-cyanophenyl, 4-methoxy-1-naphthyl, 4-nitrophenyl, 4-pyridinyl, 5-(4'"'"'-methoxybenzyl)-furan-2-yl, 5-bromo-4-hydroxy-3-methoxyphenyl, 5-nitro-2-furyl, 6-methyl-2-pyridinyl and phenyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is 1-aminomethyladamantanyl; and

Y is C(O)NH₂.

12. The library of claims 10 or 11 wherein R² is 5-(4'"'"'-methoxybenzyl)-furan-2-yl.

11. An isoquinoline library of an approximately equimolar mixture of two or more compounds of the formula:

##STR25## wherein;

R¹ is selected from the group consisting of methylene, 1,2-ethyl, 1,4-butyl, 1,6-hexyl, (s)-1-(amino)-1,2-ethyl, (s)-1-(amino)-1,5-pentyl, (r)-(1-methyl)-1,2-ethyl, (s)-(1-(methyl)-1,2 ethyl), ##STR26## R² is selected from the group consisting of 1,4-benzodioxan-6-yl, 1-methylindole-3-yl, 2,3-difluorophenyl, 2-bromophenyl, 2-chloro-5-nitrophenyl, 2-furyl, 2-imidazolyl, 2-naphthyl, 2-pyridinyl, 2-thiophen-yl, 3,4-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dimethyl-4-hydroxyphenyl, 3-(4-methoxyphenoxy)phenyl, 3-furyl, 3-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 3-methylphenyl, 3-nitrophenyl, 3-pyridinyl, 3-thiophen-yl, 4-(3-dimethylaminopropoxy)phenyl, 4-(dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(trifluoromethyl)phenyl, 4-biphenyl, 4-bromo-2-thiophenyl, 4-cyanophenyl, 4-methoxy-1-naphthyl, 4-nitrophenyl, 4-pyridinyl, 5-(4'"'"'-methoxybenzyl)-furan-2-yl, 5-bromo-4-hydroxy-3-methoxyphenyl, 5-nitro-2-furyl, 6-methyl-2-pyridinyl and phenyl;

R³, R⁴, R⁵, R⁶ are independently a hydrogen atom;

X is (aminomethyl)cyclohexyl; and

Y is C(O)NH₂.